Degeneration of specific types of neurons in the central nervous system (CNS) or the enteric nervous system (ENS) results in several major disorders. In Parkinson""s disease (PD), dopaminergic neurons are lost in the substanita nigra of the brain, leading to impairment of coordination of skeletal muscle movement. It has been demonstrated that there is a loss of dopaminergic neurons in the colon of PD patients with constipation. In achalasia, Hirschsprung""s disease, and congenital pyloric stenosis, loss of nitric oxide-producing neurons (nitrinergic) is well documented. This nitrinergic loss leads to the inability of the gastrointestinal (GI) smooth muscle to relax, resulting in severe motility disorders.
An exciting new strategy of treatment is to replace these losses by implanting neurons into the affected areas. For example, implantation of fetal neurons into the brain of PD patients has resulted in the improvement of motor function. However, anatomical and functional contacts of these implanted cells with striatal neurons could not be clearly demonstrated because of difficulty in identifying the implanted neurons and because no functional assay for connectivity was available. Use of fetal tissue has severe limitations. The supply of human fetal tissue is restricted and a potential exists for host/graft rejection of the implanted neurons.
Neurodegenerative disorders of the CNS, such as PD, Alzheimer""s disease, multiple sclerosis, and Huntington""s disease are common problems in clinical practice. Besides the well-known enteric nervous degenerative disorders such as achalasia, Hirschsprung""s disease, and congenital pyloric stenosis, several other common gastrointestinal disorders, e.g., reflux disease, irritable bowel syndrome, and intestinal pseudo-obstruction are increasingly recognized as related to disordered enteric neurons.
The enteric nervous system (ENS) is apart of the peripheral nervous system and consists of neuronal cell bodies, their fibers, and supporting cells located within the wall of the GI tract. These cell bodies are arranged in two major ganglionated plexuses, a peripheral myenteric (Aucibach""s) between the circular and the longitudinal muscle layers, and a submucosal (Meissner""s) plexus in the submucosal connective tissue between tire muscularis mucosa and circular muscle. For the most part, the myenteric neurons provide excitatory (acetylcholine and substance P) and inhibitory (nitric oxide, VIP, CORP, and ATP) transmitters to the gut smooth muscle. The tone of the gut muscle depends on the summated influence of the opposing actions of these neurotransmitters.
Current treatment options for neurodegenerative gastrointestinal disorders are very limited. Thus, there is a need for new treatment protocols for gastrointestinal disorders that involve neurons, muscle tissue, or other tissues, as well as other disorders that are related to gastrointestinal organs.
The present invention is directed to a method for the treatment of disorders using stem cells and/or progeny thereof for implantation into a gastrointestinal organ of a subject (preferably, a mammal, and more preferably, a human). The spectrum of disorders in which such treatment will be useful includes, but is not limited to, degenerative, immunologic/inflammatory, neoplastic, and idiopathic conditions of the gastrointestinal tract that may be either congenital or acquired. Thus, the disorders include any of a variety of gastrointestinal disorders that involve, for example, neurons as well as muscle tissue, although other tissues can be involved as well. Other disorders that are related to the function or dysfunction of a gastrointestinal organ can also be treated using the method of the present invention.
Gastrointestinal organs include hollow and solid organs. Hollow gastrointestinal organs include those that make up the alimentary tract, such as the mouth, esophagus, stomach, and bowels. Solid gastrointestinal organs include those that drain into the gastrointestinal alimentary tract, such as the liver, gall bladder, and pancreas.
As used herein, treating a gastrointestinal disorder includes both therapeutic and prophylactic (i.e., preventive) treatment. The success of such a treatment can be determined by evaluation of the functional status of an organ or a patient as determined by clinical outcome and/or morphological analysis.
Specifically, the present invention provides a method of implantation (e.g., transplantation) of stem cells (preferably, multipotent or totipotent stem cells) into a gastrointestinal organ (e.g., the gastrointestinal alimentary tract or solid organs that drain into the alimentary tract) for purposes of repopulating various cellular components (such as the neurons, muscles, or other cell types) and/or providing a source of biological material (e.g., neurotransmitters, cytokines, anticytokines, growth factors, immune modulators, antiinflammtory agents, antineoplastic agents, analgesics, etc.) for therapeutic intent. The source of these stem cells can be embryonic or adult neural and non-neural tissue (e.g., bone marrow or fat tissue).
The implantation can be carried out via local injection, as for example into a wall of the gastrointestinal tract or into a solid gastrointestinal organ such as the pancreas or liver, by administration into the systemic (e.g., via the blood stream or the peritoneal cavity) or portal circulation system, or by any other practical means.
The present invention also provides a method of producing enhanced levels of insulin in a patient. This involves implanting stem cells and/or progeny thereof into the pancreas, which is considered a gastrointestinal organ as used herein because it is a solid organ that drains into the gastrointestinal alimentary tract.